The Epstein-Barr virus (EBV) genome contains an open reading frame, BHRF1, that encodes a presumptive membrane protein with sequence similarity to the proto-oncogene bcl2, which is linked to human B-cell follicular lymphoma.
Detection of rearrangements of the BCL2 major breakpoint region in follicular lymphomas. Correlation of polymerase chain reaction results with Southern blot analysis.
While all proliferating cells expressed both genes, BCL2 expression was increased two- to threefold in follicular lymphomas with t(14;18) and MYC expression was increased two- to four-fold in high-grade lymphomas with t(8;14).
The bcl-2 gene is translocated into the Ig loci in about 80% of human follicular lymphomas and in 10% of B-type chronic lymphocytic leukemias (B-CLL), resulting in a high level of expression.
Thus, additional steps must be involved in the clonal expansion of the FL tumor cell beyond the activation of bcl-2 as a consequence of the t(14;18) translocation.
In non-malignant tissues, the polymerase chain reaction was used to study the frequency of bcl-2/IgH rearrangements in reactive lymphoid tissue obtained from American and Japanese patients to find out whether geographic variation in the incidence of follicular lymphoma was caused by differences in sporadic occurrence of the t(14;18).
All 18 pretransformation follicular lymphoma specimens displayed at least one immunoglobulin gene and BCL-2 rearrangement in common with the corresponding histologically progressed lymphoma, indicating a clonal relationship between the original follicular lymphoma and the histologically transformed lymphoma.
The bcl-2 gene, encoding a mitochondrial membrane protein suggested to play an important role in cell survival, is translocated into the Ig loci in about 80% of human follicular lymphomas, which results in a high level of expression.
Sequence analysis showed the amplified bcl-2/JH fragments to be unique to each individual sample and distinct from 24 sequenced follicular lymphoma-derived t(14;18) junctions, thus excluding contamination artifacts.
The pattern of Bcl-2 staining in follicular lymphoma is the inverse of the pattern in reactive hyperplasia, confirming a role for Bcl-2 immunolocalization in routine diagnosis.
Chromosomal translocations involving the heavy chain immunoglobulin locus on chromosome 14 and a region on chromosome 18 encoding the bcl-2 gene [t(14;18)] are a characteristic and prevalent chromosomal abnormality in nodal malignant lymphoma, particularly follicular lymphoma.
The bcl-3 pattern of expression also bears close resemblance to that of bcl-2 (Gurfinkel et al., 1987), which is frequently associated with human B follicular lymphomas [t(14; 18)] and some chronic lymphocytic leukemias (Adachi et al., 1989; 1990; Adachi & Tsujimoto, 1989).
Most of human follicular lymphomas possess the t(14;18) chromosome translocation that juxtaposes the IgH gene to the 3' region of bcl-2 in a head-to-tail configuration.
To determine the relative importance of these mutations, we searched for their presence in DNA from the involved lymph nodes of 12 patients with t(14; 18) follicular lymphoma. bcl-2 genomic sequences were specifically amplified by the polymerase chain reaction technique and then directly sequenced.
That bcl-2 is involved in a major class of lymphoma in addition to follicular lymphoma implies a role for additional factors responsible for generating the two distinctive clinical and pathologic disease states.
In the present study we confirmed, by immunohistologic labeling with polyclonal and monoclonal antibodies, that bcl-2 protein is strongly expressed in many cases of follicular lymphoma and that these neoplastic follicles differ clearly from their nonmalignant counterpart (reactive germinal centres) in which bcl-2 protein is undetectable.